Author's Take

In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The JCI accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the
Author's Take Guidelines page.

Macrophage polarization in response to stimuli within the microenvironment results in heterogeneous populations that can differentially influence disease. Atherosclerosis is largely inflammatory, with lipids driving polarization of M1 macrophages; however, alternatively activated, hemoglobin-scavenging CD163+ macrophages are present within atherosclerotic lesions and have been proposed to serve an antiinflammatory role. In this episode, Aloke Finn and Liang Guo discuss their work, which shows that CD163+ macrophages actually promote angiogenesis, vessel permeability, and leucocyte infiltration, thereby exacerbating plaque progression. The pathogenic effects of this alternatively activated population were driven by HIF1α/VEGF-A signaling, suggesting this pathway as a potential therapeutic target.

As primary tumor progression to metastasis dramatically increases mortality in patients with cancer, strategies to limit tumor cell growth and spread are of great interest. The orphan receptor tyrosine kinase Tie1 is highly expressed in intratumoral vasculature; however, the contribution of this receptor to tumor progression has not been defined. In this episode, Hellmut Augustin and Silvia La Porta, aided by original artwork by Carleen Spegg, discuss their work, which shows that loss of Tie1 in endothelial cells reduces primary tumor progression and limits metastasis. The results of this study indicate that Tie1 should be further explored as a therapeutic target for limiting cancer progression.

Melanoma-directed immunotherapies have improved quality of life and outcome for many patients with this malignancy. Unfortunately, treatment resistance develops in some individuals and other patients do not respond to therapy; therefore, there remains a need for additional intervention targets for this devastating disease. In this episode, Craig Ceol and Arvind Venkatesan discuss their recent study, which identifies GDF6-mediated BMP signaling as a driver of melanoma. Importantly, upregulation of this GDF6 in patients with melanoma associated with increased metastasis and decreased survival, supporting further development of strategies to target GDF6/BMP signaling.

Pathogenic remodeling following heart injury is due, in part, to the limited regenerative capacity of adult cardiomyocytes. Cell cycle induction has been recently explored as a therapeutic approach for heart failure, and to this end, expression of cyclin D2 in cardiomyocytes improves outcomes in mouse models follwoing myocardial infarction. In this episode, Gerd Hasenfuß, Loren Field, and Karl Toischer discuss their collaborative effort to further evaluate the effect of increased cyclin D2 on outcomes in response to other forms of heart failure. Cyclin D2 expression improved survival and cardiac function in mice exposed to pressure overload; however, cyclin D2-espressing mice were not protected from adverse effects in response to chronic volume overload. These results support further effort into the development of strategies to improve cardiomyocyte proliferation for some types cardiac injury.

Necrotizing enterocolitis is a leading cause of death in preterm infants and is characterized by severe inflammation. The incidence of necrotizing enterocolitis is reduced in preterm infants fed human breast milk; however, the factors underlying the beneficial effects of human breast milk are not fully understood. In this episode, Mansour Mohamadzadeh and colleagues compared the microbiome of preterm infants fed either breast milk or formula and identified a propionobacterial strain (P. FU1) that was present in the gut microbiota of breastmilk fed- but not formula fed-infants. Moreover, introduction of this bacterial strain into murine models was protective against necrotizing enterocolitis-like inflammation and injury as well pathogenic intestinal pathogens. The results of this study provide important insight into the beneficial effects of human breast milk on intestinal flora.